Mechanisms of cognitive impairment in epilepsy

Thesis

Cognitive impairment and dementia are increasingly reported as people with epilepsy grow older, with major impact on quality of life. The underlying mechanisms of cognitive dysfunction, however, and the magnitude of associated dementia risk in epilepsy remains unclear. This thesis will explore how cardiovascular risk factors and hippocampal dysfunction are two important mechanistic links between epilepsy and dementia.

Using data from a large population-based cohort, the studies in this thesis demonstrate that cardiovascular risk factors are closely related to impairment of executive function. One finding highlighted a continuous dose-response relation of cognition with blood pressure, even in non-hypertensive individuals. The relationship between cardiovascular risk and cognition was mediated through changes in both frontoparietal white and grey matter structural networks. In the same cohort, people with epilepsy and a high cardiovascular risk were over 13 times more likely to develop dementia compared to healthy controls with low cardiovascular risk. People with epilepsy had a greater risk of developing dementia even compared with individuals with a history of stroke, with associated changes to hippocampal volume.

To examine specific hippocampal-related cognitive mechanisms that may underlie memory difficulties in epilepsy, I examined two processes believed to be central to encoding and retrieval in the hippocampus: pattern separation and pattern completion. I devised a novel computer-based behavioural paradigm called the Memory Pinhole Task to distinguish them. Impairment of these two cognitive operations have been identified in ageing and other conditions such as Alzheimer’s disease. Compared to healthy controls, pattern separation deficits were observed in people with epilepsy while reduced pattern completion was seen in healthy older individuals. I then mapped these findings from the Memory Pinhole task onto potential brain mechanisms through computational modelling using a neural network.

The work in this thesis describes how modifiable cardiovascular risk factors significantly contribute to cognitive ageing and dementia risk in healthy individuals and people with epilepsy. This has important implications for personal health practices and clinical guidelines, especially in people with epilepsy as there is no current guidance to mitigate dementia risk. Further, I describe a framework for testing encoding and retrieval of information into memory which may allow us to better understand difficulties seen in both health and disease.

Authors: Tai, XY

• DOI: 10.5287/ora-nzxejjr5q
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: dementia; cognitive impairment; epilepsy
• Subjects: Neurology; Memory; Epilepsy; Dementia